Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

详细信息    查看全文

• 作者：Travis T. Wager ; Thomas Chappie ; David Horton ; Ramalakshmi Y. Chandrasekaran ; Brian Samas ; Elizabeth R. Dunn-Sims ; Cathleen Hsu ; Nawshaba Nawreen ; Michelle A. Vanase-Frawley ; Rebecca E. O’Connor ; Christopher J. Schmidt ; Keith Dlugolenski ; Nancy C. Stratman ; Mark J. Majchrzak ; Bethany L. Kormos ; David P. Nguyen ; Aarti Sawant-Basak ; Andy N. Mead
• 刊名：ACS Chemical Neuroscience
• 出版年：2017
• 出版时间：January 18, 2017
• 年：2017
• 卷：8
• 期：1
• 页码：165-177
• 全文大小：620K
• ISSN：1948-7193

文摘

Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 K_i = 3.1 nM), good subtype selectivity over D2R (D2 K_i = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3 has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.